Hitting the hidden: arming the immune system for the next zoonotic coronavirus spillover
Charlie Fricke, Stanley Perlman
Charlie Fricke, Stanley Perlman
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Commentary

Hitting the hidden: arming the immune system for the next zoonotic coronavirus spillover

Abstract

Coronaviruses, both known and yet to emerge, pose persistent zoonotic and pandemic threats. While current parenteral COVID-19 mRNA vaccines effectively mitigate severe disease caused by SARS-CoV-2, they primarily elicit systemic immunity restricted to specific variants within clade 1b of the sarbecovirus subgenus and provide limited mucosal protection. Addressing these shortcomings, Cheang et al. developed a DC-targeting intranasal booster vaccine that induces robust and durable mucosal and systemic immunity across sarbecovirus clades 1a and 1b. This study highlights a promising strategy for pan-sarbecovirus vaccines by leveraging mucosal immune induction to prevent viral transmission and enhance pandemic preparedness.

Authors

Charlie Fricke, Stanley Perlman

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Figure 1

Mechanism of Clec9A-targeted vaccine–induced immunity.

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Mechanism of Clec9A-targeted vaccine–induced immunity. The bivalent muco...
The bivalent mucosal booster vaccine developed by Cheang et al. utilized Clec9A-targeted delivery of SARS-CoV-2 RBD to cDC1s, enabling humoral and cellular immune activation (5). (i) The αClec9A–RBD fusion antibody binds Clec9A on cDC1s, facilitating efficient antigen uptake and processing. (ii) Processed antigens are cross-presented via MHC class I (MHCI) to CD8+ T cells and presented via MHC class II (MHCII) to CD4+ T cells, inducing cytotoxic and helper functions, respectively. (iii) Tfh–B cell interactions promote GC B cell activation and affinity maturation. (iv) GC B cells differentiate into plasma cells that secrete high-affinity neutralizing antibodies. (v) These antibodies neutralize SARS-CoV-2, while CD8+ T cell–mediated cytolysis contributes to durable, cross-protective immunity.